Volume 15 Issue 1
Jan.  2024
Turn off MathJax
Article Contents
Article Navigation >  ORGAN TRANSPLANTATION  > 2024  >  15(1): 46-54
Peng Xuan, Ni Haiqiang, Gu Shiqi, et al. Down-regulation of XBP1s alleviates the senescence of renal tubular epithelial cells induced by hypoxia/reoxygenation through Sirt3/SOD2/mtROS signaling pathway[J]. ORGAN TRANSPLANTATION, 2024, 15(1): 46-54. doi: 10.3969/j.issn.1674-7445.2023186
Citation: Peng Xuan, Ni Haiqiang, Gu Shiqi, et al. Down-regulation of XBP1s alleviates the senescence of renal tubular epithelial cells induced by hypoxia/reoxygenation through Sirt3/SOD2/mtROS signaling pathway[J]. ORGAN TRANSPLANTATION, 2024, 15(1): 46-54. doi: 10.3969/j.issn.1674-7445.2023186
shu

Down-regulation of XBP1s alleviates the senescence of renal tubular epithelial cells induced by hypoxia/reoxygenation through Sirt3/SOD2/mtROS signaling pathway

doi: 10.3969/j.issn.1674-7445.2023186

  • Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, Key Laboratory of Organ Transplantation of National Health Commission of China, Key Laboratory of Organ Transplantation of Chinese Academy of Medical Sciences, Wuhan 430030, China

More Information
  • Corresponding author: Gong Nianqiao, Email: nqgong@tjh.tjmu.edu.cn
  • Received Date: 2023-09-20
    Available Online: 2023-11-29
  • Publish Date: 2024-01-11
    Abstract
  •   Objective  To investigate the role and mechanism of spliced X-box binding protein 1 (XBP1s) in the senescence of primary renal tubular epithelial cells induced by hypoxia/reoxygenation (H/R).   Methods  Primary renal tubular epithelial cells were divided into the normal control group (NC group), H/R group, empty adenovirus negative control group (Ad-shNC group), targeted silencing XBP1s adenovirus group (Ad-shXBP1s group), empty adenovirus+H/R treatment group (Ad-shNC+H/R group) and targeted silencing XBP1s adenovirus+H/R treatment group (Ad-shXBP1s +H/R group), respectively. The expression levels of XBP1s in the NC, H/R, Ad-shNC and Ad-shXBP1s groups were measured. The number of cells stained with β-galactosidase, the expression levels of cell aging markers including p53, p21 and γH2AX, and the levels of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) were determined in the Ad-shNC, Ad-shNC+H/R and Ad-shXBP1s+H/R groups. Chromatin immunoprecipitation was employed to verify Sirtuin 3 (Sirt3) of XBP1s transcription regulation, and the expression levels of Sirt3 and downstream SOD2 after down-regulation of XBP1s were detected. Mitochondrial reactive oxygen species (mtROS) were detected by flow cytometry.   Results  Compared with the NC group, the expression level of XBP1s was up-regulated in the H/R group. Compared with the Ad-shNC group, the expression level of XBP1s was down-regulated in the Ad-shXBP1s group (both P<0.001). Compared with the Ad-shNC group, the number of cells stained with β-galactosidase was increased, the expression levels of p53, p21 and γH2AX were up-regulated, the levels of ROS, MDA and mtROS were increased, the SOD activity was decreased, the expression level of Sirt3 was down-regulated, and the ratio of Ac-SOD2/SOD2 was increased in the Ad-shNC+H/R group. Compared with the Ad-shNC+H/R group, the number of cells stained with β-galactosidase was decreased, the expression levels of p53, p21 and γH2AX were down-regulated, the levels of ROS, MDA and mtROS were decreased, the SOD activity was increased, the expression level of Sirt3 was up-regulated and the ratio of Ac-SOD2/SOD2 was decreased in the Ad-shXBP1s+H/R group (all P<0.05).   Conclusions  Down-regulation of XBP1s may ameliorate the senescence of primary renal tubular epithelial cells induced by H/R, which probably plays a role through the Sirt3/SOD2/mtROS signaling pathway.

     

    • FullText(HTML)
  • loading
    • References(38)
  • [1]
    PONTICELLI C, REGGIANI F, MORONI G. Delayed graft function in kidney transplant: risk factors, consequences and prevention strategies[J]. J Pers Med, 2022, 12(10): 1557. DOI: 10.3390/jpm12101557.
    [2]
    GRANATA S, VOTRICO V, SPADACCINO F, et al. Oxidative stress and ischemia/reperfusion injury in kidney transplantation: focus on ferroptosis, mitophagy and new antioxidants[J]. Antioxidants (Basel), 2022, 11(4): 769. DOI: 10.3390/antiox11040769.
    [3]
    李晓凤, 张国欣, 杨开银, 等. 核因子E2相关因子2在肾缺血-再灌注损伤中的作用[J]. 器官移植, 2023, 14(5): 656-661. DOI: 10.3969/j.issn.1674-7445.2023124.

    LI XF, ZHANG GX, YANG KY, et al. Effect of nuclear factor E2-related factor 2 on renal ischemia-reperfusion injury[J]. Organ Transplant, 2023, 14(5): 656-661. DOI: 10.3969/j.issn.1674-7445.2023124.
    [4]
    CHEN C, ZHENG M, HOU H, et al. Cellular senescence in ischemia/reperfusion injury[J]. Cell Death Discov, 2022, 8(1): 420. DOI: 10.1038/s41420-022-01205-z.
    [5]
    DOCHERTY MH, O'SULLIVAN ED, BONVENTRE JV, et al. Cellular senescence in the kidney[J]. J Am Soc Nephrol, 2019, 30(5): 726-736. DOI: 10.1681/ASN.2018121251.
    [6]
    郑博文, 刘华亭, 范晓阳, 等. 肾小管上皮细胞损伤促进肾纤维化的研究进展[J]. 中国医药科学, 2023, 13(7): 54-57. DOI: 10.3969/j.issn.2095-0616.2023.07.015.

    ZHENG BW, LIU HT, FAN XY, et al. Research progress of renal tubular epithelial cells injury in promoting renal fibrosis[J]. China Med Pharm, 2023, 13(7): 54-57. DOI: 10.3969/j.issn.2095-0616.2023.07.015.
    [7]
    YAN M, SHU S, GUO C, et al. Endoplasmic reticulum stress in ischemic and nephrotoxic acute kidney injury[J]. Ann Med, 2018, 50(5): 381-390. DOI: 10.1080/07853890.2018.1489142.
    [8]
    王立堃, 李桃, 徐芬芬. 未折叠蛋白响应的激活机制[J]. 生物化学与生物物理进展, 2023, 50(5): 877-891. DOI: 10.16476/j.pibb.2023.0137.

    WANG LK, LI T, XU FF, et al. The mechanism of the unfolded protein response activation[J]. Prog Biochem Biophys, 2023, 50(5): 877-891. DOI: 10.16476/j.pibb.2023.0137.
    [9]
    CHEN Y, BRANDIZZI F. IRE1: ER stress sensor and cell fate executor[J]. Trends Cell Biol, 2013, 23(11): 547-555. DOI: 10.1016/j.tcb.2013.06.005.
    [10]
    PARK SM, KANG TI, SO JS. Roles of XBP1s in transcriptional regulation of target genes[J]. Biomedicines, 2021, 9(7): 791. DOI: 10.3390/biomedicines9070791.
    [11]
    NI H, OU Z, WANG Y, et al. XBP1 modulates endoplasmic reticulum and mitochondria crosstalk via regulating NLRP3 in renal ischemia/reperfusion injury[J]. Cell Death Discov, 2023, 9(1): 69. DOI: 10.1038/s41420-023-01360-x.
    [12]
    GAO J, FENG Z, WANG X, et al. Sirt3/SOD2 maintains osteoblast differentiation and bone formation by regulating mitochondrial stress[J]. Cell Death Differ, 2018, 25(2): 229-240. DOI: 10.1038/cdd.2017.144.
    [13]
    TAO R, VASSILOPOULOS A, PARISIADOU L, et al. Regulation of MnSOD enzymatic activity by Sirt3 connects the mitochondrial acetylome signaling networks to aging and carcinogenesis[J]. Antioxid Redox Signal, 2014, 20(10): 1646-1654. DOI: 10.1089/ars.2013.5482.
    [14]
    QIU X, BROWN K, HIRSCHEY MD, et al. Calorie restriction reduces oxidative stress by Sirt3-mediated SOD2 activation[J]. Cell Metab, 2010, 12(6): 662-667. DOI: 10.1016/j.cmet.2010.11.015.
    [15]
    ZHU M, HE J, XU Y, et al. AMPK activation coupling SENP1-Sirt3 axis protects against acute kidney injury[J]. Mol Ther, 2023, 31(10): 3052-3066. DOI: 10.1016/j.ymthe.2023.08.014.
    [16]
    ELEFTHERIADIS T, PISSAS G, FILIPPIDIS G, et al. The role of indoleamine 2, 3-dioxygenase in renal tubular epithelial cells senescence under anoxia or reoxygenation[J]. Biomolecules, 2021, 11(10): 1522. DOI: 10.3390/biom11101522.
    [17]
    LUO C, ZHOU S, ZHOU Z, et al. Wnt9a promotes renal fibrosis by accelerating cellular senescence in tubular epithelial cells[J]. J Am Soc Nephrol, 2018, 29(4): 1238-1256. DOI: 10.1681/ASN.2017050574.
    [18]
    VALENTIJN FA, KNOPPERT SN, MARQUEZ-EXPOSITO L, et al. Cellular communication network 2 (connective tissue growth factor) aggravates acute DNA damage and subsequent DNA damage response-senescence-fibrosis following kidney ischemia reperfusion injury[J]. Kidney Int, 2022, 102(6): 1305-1319. DOI: 10.1016/j.kint.2022.06.030.
    [19]
    CHEN J, LU H, WANG X, et al. VNN1 contributes to the acute kidney injury-chronic kidney disease transition by promoting cellular senescence via affecting RB1 expression[J]. FASEB J, 2022, 36(9): e22472. DOI: 10.1096/fj.202200496RR.
    [20]
    LI C, SHEN Y, HUANG L, et al. Senolytic therapy ameliorates renal fibrosis postacute kidney injury by alleviating renal senescence[J]. FASEB J, 2021, 35(1): e21229. DOI: 10.1096/fj.202001855RR.
    [21]
    ZHANG J, ZHANG J, NI H, et al. Downregulation of XBP1 protects kidney against ischemia-reperfusion injury via suppressing HRD1-mediated NRF2 ubiquitylation[J]. Cell Death Discov, 2021, 7(1): 44. DOI: 10.1038/s41420-021-00425-z.
    [22]
    ZHANG J, XIANG H, LIU J, et al. Mitochondrial sirtuin 3: new emerging biological function and therapeutic target[J]. Theranostics, 2020, 10(18): 8315-8342. DOI: 10.7150/thno.45922.
    [23]
    WANG D, CAO L, ZHOU X, et al. Mitigation of honokiol on fluoride-induced mitochondrial oxidative stress, mitochondrial dysfunction, and cognitive deficits through activating AMPK/PGC-1α/Sirt3[J]. J Hazard Mater, 2022, 437: 129381. DOI: 10.1016/j.jhazmat.2022.129381.
    [24]
    XIAO L, FANG Z, WANG Q, et al. Curcumin ameliorates age-induced tight junction impaired in porcine sertoli cells by inactivating the NLRP3 inflammasome through the AMPK/Sirt3/SOD2/mtROS signaling pathway[J]. Oxid Med Cell Longev, 2023: 1708251. DOI: 10.1155/2023/1708251.
    [25]
    ELEFTHERIADIS T, PISSAS G, GOLFINOPOULOS S, et al. Inhibition of malate dehydrogenase-2 protects renal tubular epithelial cells from anoxia-reoxygenation-induced death or senescence[J]. Biomolecules, 2022, 12(10): 1415. DOI: 10.3390/biom12101415.
    [26]
    QIN Z, WANG H, DOU Q, et al. Protective effect of fluoxetine against oxidative stress induced by renal ischemia-reperfusion injury via the regulation of miR-450b-5p/Nrf2 axis[J]. Aging (Albany NY), 2022,DOI: 10.18632/aging.204289[Epub ahead of print
    [27]
    CABRAL-MIRANDA F, TAMBURINI G, MARTINEZ G, et al. Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging[J]. EMBO J, 2022, 41(22): e111952. DOI: 10.15252/embj.2022111952.
    [28]
    HUANG C, WU S, JI H, et al. Identification of XBP1-u as a novel regulator of the MDM2/p53 axis using an shRNA library[J]. Sci Adv, 2017, 3(10): e1701383. DOI: 10.1126/sciadv.1701383.
    [29]
    WU QJ, ZHANG TN, CHEN HH, et al. The sirtuin family in health and disease[J]. Signal Transduct Target Ther, 2022, 7(1): 402. DOI: 10.1038/s41392-022-01257-8.
    [30]
    白玉杰, 王建辉, 吴东颖. 烟酰胺腺嘌呤二核苷酸和Sirtuins在衰老和疾病中的作用[J]. 中国生物化学与分子生物学报, 2022, 38(10): 1294-1303. DOI: 10.13865/j.cnki.cjbmb.2022.04.1562.

    BAI YJ, WANG JH, WU DY. Roles of NAD+ and sirtuins in aging and disease[J]. Chin J Biochem Mol Biol, 2022, 38(10): 1294-1303. DOI: 10.13865/j.cnki.cjbmb.2022.04.1562.
    [31]
    SUNG JY, KIM SG, KANG YJ, et al. Metformin mitigates stress-induced premature senescence by upregulating AMPKα at Ser485 phosphorylation induced Sirt3 expression and inactivating mitochondrial oxidants[J]. Mech Ageing Dev, 2022, 206: 111708. DOI: 10.1016/j.mad.2022.111708.
    [32]
    MIAO HH, LIU Q, WANG N, et al. The effect of Sirt3/Ac-SOD2 mediated oxidative stress and HCN1 channel activity on anesthesia/surgery induced anxiety-like behavior in mice[J]. Front Med (Lausanne), 2022, 9: 783931. DOI: 10.3389/fmed.2022.783931.
    [33]
    刘恋, 夏中元, 李冰玉, 等. Sirt3过表达对高糖小鼠海马神经元缺氧复氧损伤的影响: 与SOD2的关系[J]. 中华麻醉学杂志, 2021, 41(5): 621-624. DOI: 10.3760/cma.j.cn131073.20210312.00526.

    LIU L, XIA ZY, LI BY, et al. Effect of Sirt3 overexpression on hypoxia-reoxygenation injury to hippocampal neurons of mice exposed to high glucose: relationship with SOD2[J]. Chin J Anesthesiol, 2021, 41(5): 621-624. DOI: 10.3760/cma.j.cn131073.20210312.00526.
    [34]
    MA LL, KONG FJ, DONG Z, et al. Hypertrophic preconditioning attenuates myocardial ischaemia-reperfusion injury by modulating Sirt3-SOD2-mROS-dependent autophagy[J]. Cell Prolif, 2021, 54(7): e13051. DOI: 10.1111/cpr.13051.
    [35]
    NING L, RUI X, GUORUI L, et al. A novel mechanism for the protection against acute lung injury by melatonin: mitochondrial quality control of lung epithelial cells is preserved through Sirt3-dependent deacetylation of SOD2[J]. Cell Mol Life Sci, 2022, 79(12): 610. DOI: 10.1007/s00018-022-04628-0.
    [36]
    CHEN ML, ZHU XH, RAN L, et al. Trimethylamine-N-oxide induces vascular inflammation by activating the NLRP3 inflammasome through the Sirt3-SOD2-mtROS signaling pathway[J]. J Am Heart Assoc, 2017, 6(9): e006347. DOI: 10.1161/JAHA.117.006347.
    [37]
    PI H, XU S, REITER RJ, et al. Sirt3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin[J]. Autophagy, 2015, 11(7): 1037-1051. DOI: 10.1080/15548627.2015.1052208.
    [38]
    LI Q, LIAO J, CHEN W, et al. NAC alleviative ferroptosis in diabetic nephropathy via maintaining mitochondrial redox homeostasis through activating Sirt3-SOD2/Gpx4 pathway[J]. Free Radic Biol Med, 2022, 187: 158-170. DOI: 10.1016/j.freeradbiomed.2022.05.024.
    • Relative Articles
    • Supplements(0)
    • Cited By
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(5)  / Tables(1)

    Get Citation
    PDF
    XML

    Article Metrics

    Article views (226) PDF downloads(40) Cited by()
    Proportional views
    Related

    WeChat Subscription Account

    Wechat Service Account

    Contact Us
    • Tel：020-38736410
    • Email: organtranspl@163.com
    • Address：The Third Affiliated Hospital of Sun Yat-sen University, No. 600, Tianhe Road, Tianhe District, Guangzhou
    • Editorial Office of Organ Transplantation  粤ICP备2021030844号
    Links

    Supported by: Beijing Renhe Information Technology Co. Ltd    

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return